Cystic fibrosis (CF) is the most common lethal inherited disease in the western world. While life expectancies have increased to nearly 40 years, respiratory failure still accounts for >80% of deaths from the disease, usually in young adults in the third or fourth decade of life. The triad of airway obstruction with mucus, chronic endobronchial infection with pathogens such as Pseudomonas aeruginosa, and severe airway inflammation, are the major pathogenic factors in CF lung disease (Konstan, 1998, Clin Chest Med 19(3):505-13, vi). Given the shortage of solid organs for transplantation in end stage lung disease, there is a critical need for effective anti-microbial and anti-inflammatory therapies to mitigate progression of disease in this young population.
However, the rendering of rapid and efficient clinical trials in CF and other diseases associated with airway inflammation, is hampered, in part, by the lack of sensitive measures of treatment response. Currently, spirometry is the most common pulmonary function test for measuring lung function. Specifically, Forced Expiratory Volume in 1 second or FEV1 is the established standard for assessing pulmonary treatment response. When FEV1 measurements are decreased, treatment is initiated. Following two to three weeks of IV antibiotic therapy, FEV1 measurements are typically repeated as a quantitative measure of clinical response. Similarly, FEV1 measurements are utilized as the gold standard measurement for treatment response in clinical trials.
Airway remodeling, driven by inflammatory cells, most directly impacts progressive decline in lung function, and ultimately survival in CF. While novel anti-inflammatory therapies seek to target this decline, fibrosis and remodeling occur slowly and progressively, and may not be detected in a typical month-long Phase 2 trial. Thus, a beneficial effect of an anti-inflammatory treatment, which slows decline in lung function via reduced fibrosis and remodeling, could be missed with monitoring of lung function by FEV1 alone.
At present, there are no known reliable and sensitive molecular markers which can be used to quantify pulmonary inflammation and assess therapeutic responses against diseases associated with such inflammation. Thus, there exists a need for development of reliable and sensitive markers of airway or pulmonary inflammation that would allow testing of therapeutics against such diseases.